Leptospirosis, a zoonotic disease caused by spirochetes of the genus Leptospira, is transmitted to humans via urine of infected mammals. Found worldwide in temperate and tropical climates, it is a public health threat in the U.S. and abroad. Human infections by Leptospira have a broad spectrum of clinical manifestations, ranging from asymptomatic seroconversion to undifferentiated febrile syndrome, with or without aseptic meningitis, to fulminant jaundice, renal failure and hemorrhage with a fatality rate up to approximately 25%. There is no vaccine to prevent human leptospirosis and veterinary vaccines may not be used in humans because of toxicity. Little is known about how this organism interacts with human lymphocytes and/or the mechanisms of leptospiral pathogenesis or immunity. We propose to examine molecular and cellular interactions of Leptospira with human peripheral blood mononuclear cells (PBMC) with a focus on different T cell populations. We have found that leptospires activate T cells in PBMC from Leptospira-naive humans, leading to proliferation and production of high IFN gamma levels. Our hypothesis is that Leptospira activation of T cells expressing the alpha/beta or gamma/delta form of the T cell receptor for antigen plays an important regulatory role in protective immunity and immunopathogenesis associated with human infections due to Leptospira spp. Our aims are to: 1) Determine the cell:cell interactions and cytokine profiles of PBMC cultures exposed to Leptospira, and characterize the phenotype, function, and specificity of T cells activated in such cultures; 2) Identify and purify Leptospira components that activate T cells; and 3) Determine the relationship between peripheral blood T cell phenotype and function and disease severity of human leptospirosis patients in an endemic region in the Peruvian Amazon. Learning how Leptospira interact with the human immune system will lead us to understand the pathogenesis of leptospirosis and how to develop vaccines and strategies to control the associated pathology.